1. Field of the Invention
This invention relates to an improved process for the 11a-dehalogenation of 11a-halo-6-demethyl-6-deoxy-6-methylenetetracyclines by treating them with a secondary or a tertiary phosphine or a tertiary phosphite.
2. Description of the Prior Art
The 11a-halo-6-demethyl-6-deoxy-6-methylenetetracyclines, referred to herein for convenience as 11-a-halo-6-methylenetetracyclines, form an important class of intermediates for further synthesis of tetracycline-type antibiotics, such as the valuable and widely used antibiotics 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline and 6.alpha.-deoxy-5-hydroxytetracycline which are prepared from 11a-chloro-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline; the former by 11a-dehalogenation and the latter by 11a-dehalogenation and reduction of the 6-methylene group.
The previously known methods for 11a-dehalogenation of 11a-halotetracyclines, including 11a-halo-6-methylenetetracyclines, are discussed in U.S. Pat. No. 3,043,875, issued July 10, 1962. These methods comprise a variety of reactions, such as treatment of the 11a-halotetracyclines:
(a) With dilute aqueous hydriodic acid, PA1 (b) With zinc metal in the presence of a proton donor, such as acetic acid, PA1 (c) In the case of 11a-bromo and 11a-iodo compounds, by boiling the product with a solvent capable of reacting with bromine or iodine (acetone, methanol, etc.), PA1 (d) Alternatively, treatment with sodium iodide in organic solvent, followed by treatment of the resultant iodo compound with metallic zinc, PA1 (e) Treatment with metal sulfites and hydrosulfites, particularly the alkali metal (Na, K, Li) salts are useful, and PA1 (f) By catalytic hydrogenation of the 11a-halotetracycline in a reaction-inert medium with hydrogen gas in the presence of a noble metal catalyst.
A further procedure, described in French Pat. No. 2,136,138, comprises electrochemical dehalogenation.
The dehalogenation of .alpha.-halo organo compounds, e.g., ketones and nitriles, by means of tertiary phosphines is reported by Borowitz et al., Tetrahedron Letters, No. 11, 471-4 (1962), Partos et al., J. Am. Chem. Soc. 87, 5068-75 (1965) and Borowitz et al., J. Org. Chem. 33, 3686-90 (1968). The use of diphenylphosphine, a secondary phosphine, as dehalogenating agent for .alpha.-haloketones is described by Borowitz et al., J. Org. Chem. 34, 2687-92 (1969). Triethylphosphite has been shown by Pudovik et al., Zhur, Obschei Khim 28, 1496-1500 (1958), (C.A. 53, 216 g) and Kreutzkamp et al., Ann. 609, 39 (1957), to function as a dehalogenating agent.
These known methods of 11a-dehalogenation of 11a-halotetracyclines are subject to disadvantages arising from the use of expensive catalysts (method f) or equipment (electrochemical dehalogenation); reaction mixtures which are frequently difficult to separate from by-products and, frequently, incomplete conversions to 11a-dehalogenated product.